Articles

Efficacy of live oral rotavirus vaccines by duration of

follow-up: a meta-regression of randomised controlled trials
Andrew Clark*, Kevin van Zandvoort*, Stefan Flasche, Colin Sanderson, Julie Bines, Jacqueline Tate, Umesh Parashar, Mark Jit

Summary
Background The duration of protection offered by rotavirus vaccines varies across the world, and this variation is Lancet Infect Dis 2019;
important to understanding and predicting the effects of the vaccines. There is now a large body of evidence on the 19: 717–27
efficacy of live oral rotavirus vaccines in different settings, but these data have never been synthesised to obtain robust Published Online
June 6, 2019
estimates of efficacy by duration of follow-up. Our aim is to estimate the efficacy of live oral rotavirus vaccines at each
http://dx.doi.org/10.1016/
point during follow-up and by mortality stratum. S1473-3099(19)30126-4
See Comment page 673
Methods In our meta-regression study, we identified all randomised controlled trials of rotavirus vaccines published *Contributed equally
until April 4, 2018, using the results of a Cochrane systematic review, and cross checked these studies against those
London School of Hygiene and
identified by another systematic review. We excluded trials that were based on special populations, trials without an Tropical Medicine, London, UK
infant schedule, and trials without clear reporting of numbers of enrolled infants and events in different periods of (A Clark PhD,
follow-up. For all reported periods of follow-up, we extracted the mean duration of follow-up (time since administration K van Zandvoort MSc,
S Flasche PhD,
of the final dose of rotavirus vaccination), the number of enrolled infants, and case counts for rotavirus-positive Prof C Sanderson PhD,
severe gastroenteritis in both non-vaccinated and vaccinated groups. We used a Bayesian hierarchical Poisson meta- Prof M Jit PhD); Murdoch
regression model to estimate the pooled cumulative vaccine efficacy (VE) and its waning with time for three mortality Children’s Research Institute,
strata. We then converted these VE estimates into instantaneous VE (iVE). Melbourne, VIC, Australia
(Prof J Bines MD); Department
of Paediatrics, The University
Findings In settings with low mortality (15 observations), iVE pooled for infant schedules of Rotarix and RotaTeq was of Melbourne, Melbourne, VIC,
98% (95% credibility interval 93–100) 2 weeks following the final dose of vaccination and 94% (87–98) after 12 months. Australia (Prof J Bines);
In medium-mortality settings (11 observations), equivalent estimates were 82% (74–92) after 2 weeks and 77% (67–84) Department of
Gastroenterology and Clinical
after 12 months. In settings with high mortality (24 observations), there were five different vaccines with observation Nutrition, Royal Children’s
points for infant schedules. The pooled iVE was 66% (48–81) after 2 weeks of follow-up and 44% (27–59) after Hospital, Melbourne, VIC,
12 months. Australia (Prof J Bines); Centers
for Disease Control and
Prevention, Atlanta, GA, USA
Interpretation Rotavirus vaccine efficacy is lower and wanes more rapidly in high-mortality settings than in (J Tate PhD, U Parashar MD); and
low-mortality settings, but the earlier peak age of disease in high-mortality settings means that live oral rotavirus Modelling and Economics Unit,
vaccines are still likely to provide substantial benefit. Public Health England, London,
UK (Prof M Jit)

Funding Bill & Melinda Gates Foundation. Correspondence to:

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
Rotavirus gastroenteritis is estimated to cause around
200 000 child deaths each year,1–3 mostly in sub-Saharan
Africa and south Asia. Episodes of rotavirus gastroenteritis
occur frequently in young children irrespective of living
standards and are a major contributor to health-care costs
worldwide.4,5
More than half of the countries in the world have
introduced rotavirus vaccines into their national
immunisation programmes.6 Infants typically receive two
oral doses of Rotarix (GlaxoSmithKline Biologicals,
London, UK) or three oral doses of RotaTeq (Merck & Co,
Kenilworth, NJ, USA) in the first 6 months of life.7,8 Both
vaccines have shown high and durable efficacy against
episodes of severe rotavirus gastroenteritis in high-income
settings but lower and less durable efficacy in sub-Saharan
Africa and south Asia.9–12 Other live oral rotavirus vaccines
are becoming available, such as ROTAVAC (Bharat
Biotech, Hyderabad, India), ROTASIIL (Serum Institute
Dr Andrew Clark, London School
of Hygiene and Tropical
Medicine, London WC1E 7HT, UK
andrew.clark@lshtm.ac.uk
of India, Pune, India), and RV3-BB (Murdoch Children’s
Research Institute, Melbourne, Australia), but these
vaccines have also reported low or waning efficacy in high-
mortality settings (eg, India, Indonesia, and Niger) when
used as part of a standard infant schedule.13–16 Alternative
schedules are being considered as one way to improve
efficacy in the second year of life. Alternatives might
involve administering the first dose at birth15 or
administering a booster dose at age 9–12 months.17
Countries considering the introduction of rotavirus
vaccine, global bodies such as WHO, and donors funding
vaccine introduction in resource-poor settings require
accurate projections of the potential effect of vaccination.
Such projections are also useful in surveillance after
vaccine introduction, to ensure that the vaccine is
performing as expected and to estimate the remaining
burden of disease after the vaccine has been introduced.
Mathematical models can predict the potential effect of
rotavirus vaccines but require credible estimates of vaccine

www.thelancet.com/infection Vol 19 July 2019 717

 Articles
Research in context
Evidence before the study
In a Cochrane systematic review published in 2012,
Soares-Weiser and colleagues identified 11 randomised
controlled trials that showed that live oral rotavirus vaccines
induce high and durable efficacy against episodes of severe
rotavirus gastroenteritis in high-income settings, but lower
and less durable efficacy in sub-Saharan Africa and south Asia.
Added value of this study
To our knowledge, this is the first study in which all the
available evidence from randomised controlled trials has been
synthesised to obtain robust estimates of efficacy by duration
of follow-up. We include several new data points from Asia
and use a novel approach to convert cumulative vaccine efficacy
into instantaneous vaccine efficacy. Our analysis provides the
most comprehensive evidence to date that rotavirus vaccine
efficacy by duration of follow-up in different settings. This
information is also crucial to the evaluation of alternative
vaccination schedules. A large body of evidence now exists
from high-quality randomised controlled trials (RCTs) in
different parts of the world, but these data have never been
pooled and synthesised to obtain robust estimates of
vaccine efficacy by duration of follow-up. Combining this
evidence is not straightforward. There is substantial
variation in trial settings, follow-up periods, sample sizes,
case definitions, and statistical methods used to calculate
CIs. In addition, the main outcome reported in RCTs is the
cumulative vaccine efficacy (VE) over a period of many
weeks, but if there is evidence of vaccine waning, then
the cumulative efficacy over the entire follow-up period
might be different to the actual instantaneous VE (iVE) at
different times within that period of follow-up.
Our aim is to estimate the instantaneous efficacy of
live oral rotavirus vaccines by duration of follow-up (time
since administration of the final dose of rotavirus
vaccination) and by mortality strata.
Methods
Search strategy and selection criteria
We ran a meta-regression, in which we included all
individual RCTs that were identified in a Cochrane
systematic review of studies published until April 8, 2018,18
and cross-checked the list against the studies identified by
a review by Lamberti and colleagues.19 AC obtained the
list of RCTs from the authors of the Cochrane review,
cross-checked the list against the studies identified by a
review by Lamberti and colleagues, extracted relevant
data, and contacted the lead investigators of the study
where further clarification was needed. A full assessment
of the risks of bias associated with each rotavirus vaccine
efficacy trial is described in detail in the Cochrane review.18
We excluded trials that were based on special populations,
trials without an infant schedule, and trials without clear
reporting of enrolled infants and events in different
718 www.thelancet.com/infection Vol 19 July 2019
efficacy is lower and wanes more rapidly in high-mortality
settings than in low-mortality settings. We show that, in
Indonesia, a neonatal schedule provides more durable
protection than the standard infant schedule, although this
analysis was based on very few case counts in each week of
follow-up.
Implications of all the available evidence
Live oral rotavirus vaccines are likely to provide substantial
benefit globally. In high-mortality settings, strategies to
optimise the effect of rotavirus vaccination warrant serious
consideration. Estimates of the instantaneous efficacy of live
oral rotavirus vaccines by duration of follow-up will be crucial
to understanding the potential effect of alternative rotavirus
vaccination schedules in different countries.
periods of follow-up. The outcome measure was efficacy
against episodes of severe rotavirus gastroenteritis, which
is the primary endpoint reported in nearly all RCTs of
rotavirus vaccines. Severe rotavirus gastroenteritis is
defined as 11–20 points on the Vesikari scale,20 or for
some older trials, 15–24 points on the Clark scale.21 If this
outcome was not reported, we used the closest available
proxy, such as efficacy against episodes of rotavirus
gastroenteritis, which involved admission to hospital or
the emergency department. In all studies, rotavirus-
positive episodes were detected by enzyme immunoassay.
This study was approved by the ethics committee
(Ref 15829) of the London School of Hygiene and Tropical
Medicine.
Follow-up definition
We extracted vaccine efficacy for all reported periods of
follow-up. Most of the studies reported results at two
follow-up points. However, we also included studies with
a single follow-up point. We extracted the number of
individuals eligible for per-protocol analysis and the
number of rotavirus-positive cases in both the non-
vaccinated and vaccinated groups. We also extracted the
mean duration of follow-up in months. We extracted per-
protocol estimates because they exclude any disease cases
reported in the first 14 days after vaccination and include
only infants who received all recommended doses. We
added 14 days to the reported mean duration of follow-up
to calculate the entire period between administration of
the last dose and the mean age at follow-up. If all infants
in a study were followed up to a specific age (eg, 12 months),
we subtracted the mean age of administration of the final
dose (or target age if the mean was not reported) from the
specific follow-up age.
Stratification of studies
To account for heterogeneity between the RCT sites, we
grouped all 201 countries in the world into quintiles

(very low mortality, low mortality, medium mortality,
high mortality, and very high mortality) using the
under-5 mortality rate reported for the period 2010–15 in
the 2017 revision of the UN Population Division database.22
We further collapsed the very low and low quintiles and
the high and very high quintiles to give three strata
for deaths under age 5 years per 1000 livebirths:
low (<13·5 deaths per 1000 livebirths), medium
(13·5–28·1 deaths per 1000 livebirths), and high
(>28·1 deaths per 1000 livebirths). Each RCT was then
assigned to a specific stratum. For RCTs with multiple
sites across several countries, we included each individual
country as a separate observation point when this was
possible. If RCT results were not disaggregated by country,
we used the sample size in each site to calculate a weighted
under-5 mortality rate and used this estimate to assign the
trial to a specific mortality stratum. We restricted the
pooled analysis to infant schedules only.
Recalculating cumulative vaccine efficacy for reported
periods of follow-up
We observed substantial variation in the way authors
estimated VE and 95% confidence intervals. Our pooled
analyses used case counts and sample sizes reported in
trials to generate credible intervals, but to ensure
consistent reporting of the data in the summary table
and plots, we also recalculated VE and 95% confidence
intervals using the method of Daly and Altman.23,24
VE was calculated as 1  – 
relative risk (RR) with
zero inflation to 0·5.25
Efficacy by duration of follow-up and mortality strata
We used a Bayesian hierarchical meta-regression model
to estimate cumulative VE by duration of follow-up. We
generated separate pooled estimates for RCTs in low
mortality, medium mortality, and high mortality strata.
We assumed that errors around the observed numbers of
cases in the unvaccinated and vaccinated groups followed
Poisson distributions. The total number of cases in the
unvaccinated group in study i and period p, termed Yi,p,u,
was estimated using the following generalised linear
model:
log(Yi,p,u) = λi,p + log (Pi,p,u)
Similarly, the total number of cases in the vaccinated
group in study i and period p, termed Yi,p,v, was estimated
using:
log(Yi,p,v) = λi,p + log (Pi,p,v) + θi(ti,p)
in which λi,p is the baseline rate of becoming infected,
Pi,p,v and Pi,p,u are the total person-months of follow-up in
the vaccinated and unvaccinated group, respectively, and
θi(ti,p) is the cumulative relative risk (RR) in study i, at
www.thelancet.com/infection Vol 19 July 2019 719
Articles
t months of follow-up. We used the log of the person-
time to estimate the log of the number of cases, so that
the person-time was used on its identity scale when
converting the cases to the identity scale. Total person-
months of follow-up was calculated as the number of
participants at the beginning of the follow-up period
multiplied by the reported mean duration of follow-up.
The hierarchical component of the model ensured that
parameter values of the study-specific RR were identical
across periods in studies with more than one data point
(eg, RR for period one and RR for period one plus two
combined).
We estimated best-fitting model parameters using
Markov Chain Monte Carlo methods. Gibbs sampling was
used to draw from posterior distributions. We used non-
informative prior distributions for all parameters. We
ran four parallel Markov Chain Monte Carlo chains and
visually assessed whether chains converged. We report
medians and 95% credible intervals from the posterior
distributions of the cumulative VE. In the absence of any
prior knowledge about the probable shape of waning, we
explored several functional forms, including linear, power
law, sigmoid, and gamma (appendix p 8). We assessed See Online for appendix
their goodness of fit using the deviance information
criterion (DIC), visual assessment, and biological
plausibility.
The best-fitting function of VE by duration of follow-up
was used to estimate the iVE by duration of follow-up
using a novel approach based on Kaplan-Meier survival
estimates. More details about the method, including a
derivation of the method, are provided in the appendix
(p 1). The iVE at time t, termed 1 – σ(t), is retrieved using
the following formula:
t–1 λ(x)
1 – σ(t) = 1 – ϑ(t) + ∫ x = 0 (ϑ(t) – σ(x)) dx
λ(t)
In this formula, iVE as a function of VE at time t is
termed 1 – σ(t), all iVEs up until time t are termed 1 – σ(x),
the baseline rate or force of infection at time t is termed
λ(t), and all baseline rates up until time t are termed λ(x).
ϑ denotes the relative rate, but we can only estimate
relative risks (θ) with our dataset. Severe rotavirus
gastroenteritis is a rare outcome, so we assume that θ is
approximately equal to ϑ.
iVE and VE are identical at time t=0, that is to say
1 – σ(0) = 1 – ϑ(0). The formula can then be used to iterate
over all VEs to retrieve iVEs. If changes in baseline rates
are not known, they can be assumed to be similar over
time, so that:
λ(x)
=1
λ(t)
For each stratum, we reported iVE at standard follow-
up times. We calculated empirical p values and credible
 Articles

intervals to investigate differences between strata. We
ran a sensitivity analysis to calculate iVE with and without
observations from trials with large sample sizes.
Analyses were done using R version 3.4.326 and the
rjags package.27 Code for the model and conversion
method is provided online.28
Head-to-head comparison of efficacy for alternative
schedules
To compare the efficacy and waning associated with
different rotavirus vaccine schedules, we identified RCTs
that directly compared different vaccine schedules head
to head and requested more detailed unpublished
information from the investigators on the number of
case counts and individuals occurring in each week of
follow-up after the last dose was administered. In sites
with available data, we fitted the same models as in the
pooled analysis but without the hierarchical parameters.
These models used the same waning functions as in the
pooled analysis (appendix, p 6) but with refitted
parameters. Again, VE by duration of follow-up was
converted to iVE, and we calculated empirical p values
and credible intervals to investigate differences between
schedules.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing
of this report. The corresponding author had full access
to all the data in the study and had final responsibility
for the decision to submit for publication.
Results
We included 50 observation points from 50 observations
published before April 4, 2018, in populations with low
under-5 mortality (15 observations), medium under-5
mortality (11 observations), and high under-5 mortality
(24 observations) (table 1). We excluded trials that
evaluated special groups, such as populations with high
HIV prevalence46 and breastfed infants.47 We excluded
the Finnish Extension Trial48,49 because the results could
not be disentangled from a pooled estimate for five
European countries reported separately.42 For the
pooled analysis we focused on infant schedules, so

Schedule Vaccine brand Score* Mean follow-up Non-vaccinated group† Vaccinated group Cumulative efficacy
(months since (95% confidence
final dose) intervals)
Mean age Doses Cases Number of Cases Number of
(weeks) individuals individuals
at dose 1
High-mortality countries
Bangladesh9 10·0 2 Rotarix V11–20 8·1 35 301 9 292 73% (45 to 87)
Malawi10 11·0 2 Rotarix V11–20 7·7 38 483 21 525 49% (15 to 70)
Malawi10 11·0 2 Rotarix V11–20 15·6 53 483 38 525 34% (2 to 56)
South Africa‡11 11·0 2 Rotarix V11–20 7·7 9 408 5 418 46% (–60 to 82)
South Africa‡11 11·0 2 Rotarix V11–20 15·6 13 408 9 418 32% (–56 to 71)
Malawi10 6·2 3 Rotarix V11–20 7·7 38 483 20 505 50% (15 to 70)
Malawi10 6·2 3 Rotarix V11–20 15·6 53 483 32 505 42% (12 to 62)
South Africa‡11 6·2 3 Rotarix V11–20 7·7 9 408 1 425 89% (16 to 99)
South Africa‡11 6·2 3 Rotarix V11–20 15·6 13 408 2 425 85% (35 to 97)
Bangladesh12 8·3 3 RotaTeq V11–20 8·0 31 565 17 563 45% (2 to 69)
Bangladesh12 8·3 3 RotaTeq V11–20 14·7 56 565 33 563 41% (11 to 61)
Ghana29 8·4 3 RotaTeq V11–20 8·0 42 1081 15 1081 64% (36 to 80)
Ghana29 8·4 3 RotaTeq V11–20 14·5 57 1081 26 1081 54% (28 to 71)
Kenya29 7·3 3 RotaTeq V11–20 8·1 12 611 2 610 83% (26 to 96)
Kenya29 7·3 3 RotaTeq V11–20 12·3 14 611 5 610 64% (1 to 87)
Mali§29 6·9 3 RotaTeq V11–20 8·5 4 921 4 921 0% (–299 to 75)
Mali29 6·9 3 RotaTeq V11–20 14·9 58 921 48 921 17% (–20 to 43)
Niger14 6·8 3 ROTASIIL V11–20 5·6 87 1728 31 1780 65% (48 to 77)
India¶13 6·9 3 ROTASIIL V11–20 8·3 94 3498 61 3527 36% (11 to 53)
India13 6·9 3 ROTASIIL V11–20 20·0 275 3502 171 3533 38% (26 o 49)
India16 6·8 3 ROTAVAC V11–20 8·2 64 2187 56 4354 56% (37 to 69)
India16 6·8 3 ROTAVAC V11–20 13·4 76 2187 71 4354 53% (35 to 66)
Indonesia||15 9·3 3 RV3-BB V11–20 7·5 17 504 4 511 77% (32 to 92)
Indonesia||15 9·3 3 RV3-BB V11–20 13·5 28 504 14 511 51% (7 to 74)
(Table 1 continues on next page)

720 www.thelancet.com/infection Vol 19 July 2019

 Articles

Schedule Vaccine brand Score* Mean follow-up Non-vaccinated group† Vaccinated group Cumulative efficacy
(months since (95% confidence
final dose) intervals)
Mean age Doses Cases Number of Cases Number of
(weeks) individuals individuals
at dose 1
(Continued from previous page)
Medium-mortality countries
China30 9·6 2 Rotarix V11–20 4·0 32 1573 8 1575 75% (46 to 88)
China30 9·6 2 Rotarix V11–20 16·5 75 1573 21 1575 72% (55 to 83)
Latin America31 (n=3) 8·4 2 Rotarix V11–20 7·5 34 454 27 1392 74% (58 to 84)
Latin America32 (n=6) 8·6 2 Rotarix V11–20 7·9 19 2099 7 4211 82% (56 to 92)
Latin America33 (n=10) 8·0 2 Rotarix V11–20 8·8 58 7081 10 7205 83% (67 to 91)
Latin America33 (n=10) 8·0 2 Rotarix V11–20 20·5 161 7081 32 7205 80% (71 to 87)
China34 8·5 3 RotaTeq V11–20 9·8 52 1946 11 1930 79% (59 to 89)
Latin America35 (n=5) 9·7 3 RotaTeq Hosp/ED 19·0 10 2237 1 2252 90% (22 to 99)
USA36 (Navajo) >6 3 RotaTeq C11–24 8·8 37 403 4 392 89% (69 to 96)
Vietnam12 9·7 3 RotaTeq V11–20 8·0 7 442 2 446 72% (–36 to 94)
Vietnam12 9·7 3 RotaTeq V11–20 12·3 15 442 5 446 67% (10 to 88)
Low-mortality countries
Europe37 (n=6) 11·5 2 Rotarix V11–20 5·3 60 1302 5 2572 96% (90 to 98)
Europe37 (n=6) 11·5 2 Rotarix V11–20 17·3 127 1302 24 2572 90% (85 to 94)
Finland38 8·3 2 Rotarix V11–20 5·3 5 123 1 245 90% (15 to 99)
Finland38 8·3 2 Rotarix V11–20 17·3 10 123 3 245 85% (46 to 96)
Japan39 7·7 2 Rotarix V11–20 20·6 12 250 2 498 92% (63 to 98)
Southeast Asia40 (n=3) 12·0 2 Rotarix V11–20 7·4 15 5256 0 5263 97% (46 to 100)
Southeast Asia40 (n=3) 12·0 2 Rotarix V11–20 31·7 64 5256 2 5263 97% (87 to 99)
Southeast Asia40 (n=3) 12·0 2 Rotarix V11–20 19·5 51 5256 2 5263 96% (84 to 99)
USA41 13·0 2 Rotarix All RVGE 7·0 18 107 2 108 89% (54 to 97)
Europe42 (n=5) 10·0 3 RotaTeq C17–24 13·3 43 1188 0 1120 99% (80 to 100)
Europe42 (n=5)¶ 10·0 3 RotaTeq C17–24 19·0 61 1155 1 1088 98% (87 to 100)
USA35 9·7 3 RotaTeq Hosp/ED 19·0 58 12 179 3 12 284 95% (84 to 98)
Finland and USA43 10·0 3 RotaTeq C17–24 4·4 6 661 0 651 92% (–38 to 100)
Japan44 7·6 3 RotaTeq C17–24 6·7 10 381 0 380 95% (19 to 100)
USA45 >8 3 RotaTeq C17–24 5·5 8 183 0 187 94% (1 to 100)
The cumulative efficacy for reported periods of follow-up after two or three doses of live oral rotavirus vaccines are shown. *Scores denote the points on the Vesikari scale 11–20 (V11–20) or Clark scale 17–24
(C17–24). All RVGE denotes any severity of rotavirus-positive gastroenteritis. Hosp/ED denotes rotavirus-positive hospitalisation or emergency department visit.†All randomised controlled trials were placebo
controlled with the exception of the Rotarix trial in Bangladesh. ‡Data only extracted for the South African cohort that was followed for two successive seasons. §There were surveillance issues in the first year of
trial in Mali that have been postulated to contribute to the low efficacy in the first period, but we did not adjust for this. ¶N values were adjusted to be the same for both follow-up periods in the Bayesian
meta-regression. ||For the neonatal schedule, the cumulative efficacy was 94% (95% CI 55–99) after about 9 months of follow-up and 75% (43–89) after about 15 months.

Table 1: Observations from published randomised controlled trials included in the pooled analysis of infant schedules

excluded the neonatal RotaShield trial50 in Ghana and
the neonatal schedule group of the RV3-BB trial15 in
Indonesia. The neonatal schedule group of the
RV3-BB trial15 was included in a separate head-to-head
comparison of the infant and neonatal schedule in
Indonesia.
Most of the data points (41 [82%] of 50) were reported
using a Vesikari score of 11–20. There were 24 data points
for Rotarix, 19 for RotaTeq, two for RV-3BB, three for
ROTASIIL, and two for ROTAVAC. More data points
(30 [60%] of 50) were based on a three-dose schedule
than a two-dose schedule (20 [40%] of 50). The mean age
of administration for the first dose ranged from
6 weeks to 13 weeks.
We estimated VE and iVE (median and 95% credible
intervals) by duration of follow-up (figure 1, table 2). In
settings with low mortality (15 observations), iVE pooled for
infant schedules of Rotarix and RotaTeq was 98%
(95% credibility interval 93–100) 2 weeks following the final
dose of vaccination and 94% (87–98) after 12 months.
Equivalent pooled estimates for medium-mortality settings
(11 observations) were 82% (74–92) after 2 weeks and
77% (67–84) after 12 months. In settings with high mortality
(24 observations), there were five vaccines with observation
points for infant schedules. The pooled iVE was 66% (48–81)
after 2 weeks of follow-up and 44% (27–59) after 12 months.
We found good evidence that iVE was significantly lower
in medium-mortality settings than in low-mortality

www.thelancet.com/infection Vol 19 July 2019 721

 Articles

Cumulative
Low mortality Medium mortality High mortality
100
•
• ••• ••
•
••
••
• • •
•• •
• •
80
• •• • • •
••
•
Vaccine efficacy (%)

60
• • • •
•
•• •• •
40
• ••
• •
20 •
0 •
−20

Instantaneous
100

80
Vaccine efficacy (%)

60

40

20

−20
2 52 104 152 2 52 104 152 2 52 104 152
Time since final dose of vaccination (weeks) Time since final dose of vaccination (weeks) Time since final dose of vaccination (weeks)

Figure 1: Median and 95% credible intervals of cumulative and instantaneous vaccine efficacy by duration of follow-up and setting after two or three doses
of oral rotavirus vaccination (infant schedules only)
A simple power function was used to represent vaccine waning over time; equivalent plots based on other potential waning functions are available in the appendix
(p 10). Each blue dot represents the VE for each observation. The size of the dot represents the relative sample size of the study. The error bars represent 95% CIs
around the VE. VE=vaccine efficacy.

Low-mortality Medium-mortality High-mortality High-mortality India

countries countries countries countries (except India)
2 weeks 98% (93 to 100) 82% (74 to 92) 66% (48–81) 81% (56–94) 54% (–78 to 88)
1 month 98% (93 to 100) 81% (74 to 90) 62% (47–75) 74% (53–88) 52% (–89 to 88)
2 months 97% (93 to 99) 80% (73 to 87) 57% (45–67) 66% (50–79) 49% (–105 to 87)
3 months 96% (92 to 99) 79% (73 to 86) 54% (44–64) 61% (48–72) 48% (–108 to 86)
6 months 95% (91 to 98) 78% (71 to 84) 49% (40–61) 49% (38–64) 45% (–115 to 86)
9 months 95% (89 to 98) 77% (69 to 84) 46% (33–60) 42% (22–61) 43% (–124 to 86)
12 months 94% (87 to 98) 77% (67 to 84) 44% (27–59) 36% (5–60) 42% (–128 to 85)
18 months 94% (83 to 97) 77% (63 to 84) 41% (17–58) 27% (–26 to 59) 41% (–135 to 85)
24 months 93% (79 to 97) 76% (59 to 83) 38% (9–58) 19% (–54 to 57) 40% (–139 to 85)
36 months 92% (69 to 97) 76% (53 to 83) 35% (–4 to 57) 7% (–107 to 56) 39% (–149 to 85)
48 months 91% (58 to 97) 75% (48 to 83) 32% (–14 to 57) –2% (–154 to 56) 38% (–154 to 85)
60 months 91% (48 to 97) 75% (44 to 83) 30% (–23 to 57) –10% (–200 to 55) 37% (–163 to 85)

Table 2: Median instantaneous vaccine efficacy and 95% credible intervals by duration of follow-up and setting after two or three doses of oral rotavirus
vaccination (infant schedules only)

settings after 2 weeks and 12 months of follow-up. The stratum. Given their large sample sizes, we investigated
median absolute percentage point difference in iVE was whether these two studies were driving the results in the
16% (95% credibility interval 4–24, p=0·0023) at 2 weeks high-mortality setting. Therefore, we ran a sensitivity
and 17% (8–28, p=0·0022) at 12 months. We found weak analysis to calculate iVE with and without the Indian
evidence that iVE was significantly lower in high-mortality data points, and for India alone (table 2; appendix p 27).
settings compared with medium-mortality settings after We found no evidence that iVE significantly differed
2 weeks and strong evidence that iVE was lower after after 2 weeks or 12 months of follow-up when excluding
12 months. The median difference was 16% (95% credibility the Indian data points from the high-mortality stratum.
interval –1 to 38, p=0·089) at 2 weeks and 33% (15 to 51, The median difference absolute percentage point differ­
p=0·0011) at 12 months. ence in iVE was –13% (95% credibility interval –39 to 16,
Two large studies in India (of ROTAVAC16 and p=0·81) after 2 weeks and 8% (–22 to 42, p=0·31) after
ROTASIIL)13 were included in the high-mortality 12 months.

722 www.thelancet.com/infection Vol 19 July 2019

 Articles

Cumulative Instantaneous
100 ••••••••••• •• Vaccine schedule
•• •
•••••••••••••••• •••••••
Neonatal
80 Infant

•••••••••••
60 •••
•••••
Vaccine efficacy

40

20

−20
0 50 100 150 0 50 100 150
Time since final dose of vaccination (weeks) Time since final dose of vaccination (weeks)

Figure 2: Median and 95% credible intervals of cumulative and instantaneous vaccine efficacy by duration of follow-up and type of schedule (neonatal vs
infant) following three doses of RV3-BB in Indonesia
A simple power function was used to represent vaccine waning over time; equivalent plots based on other potential waning functions are available in the appendix
(p 19). Data points shown on the left-hand panel represent observed vaccine efficacies derived from cumulative Kaplan-Meier hazard ratios, and error bars with their
corresponding 95% confidence intervals. Solid lines and dashed lines represent medians. Shaded areas represent 95% credible intervals.

A simple power function was fitted in all strata because schedules of Rotarix in South Africa and Malawi. We were
this required the fewest assumptions and parameters and unable to obtain the underlying dataset for this trial. In
had goodness of fit (DIC scores) that were consistently both countries, a three-dose schedule (administered at
favourable across all strata of interest compared with 6 weeks, 10 weeks, and 14 weeks) had higher VE than the
other functions (appendix p 8). Results for alternative two-dose schedule (administered at 10 weeks and
functions are shown in the appendix (p 10). 14 weeks), but the CIs were wide (table 1).
We found few RCTs with head-to-head comparisons of
different schedules. In Indonesia, a three-dose neonatal Discussion
RV3-BB schedule (administered at 0–5 days, 8–10 weeks, Our analysis showed that live oral rotavirus vaccines
and 14–16 weeks) was compared with a three-dose RV3-BB provide high and durable protection in low-mortality and
infant schedule (administered at 8–10 weeks, 14–16 weeks, medium-mortality settings. Efficacy is lower and wanes
and 18–20 weeks).15 For the neonatal schedule, the VE was more rapidly in high-mortality settings, but in these
94% (95% confidence interval 55–99) after about 9 months settings, more than 60% of rotavirus gastroenteritis
of follow-up and 75% (43–89) after about 15 months. For hospital admissions occur before age 1 year, and more
the infant schedule, VE was 77% (32–92) after about than 90% occur before age 2 years.51 Thus, live oral
8 months and 51% (7–74) after about 14 months (table 1). rotavirus vaccines are still likely to provide substantial
For this trial, we were able to obtain the number of events benefit in these settings, irrespective of waning.
in each week of follow-up to better inform estimates of iVE The reasons for lower rotavirus vaccine efficacy in
over time. For the neonatal schedule, the estimated iVE resource-poor settings are not well understood.
was 98% (92–100) after 2 weeks, 77% (73–80) after 6 months, Immunogenicity studies have shown lower geometric
and 57% (42–69) after 12 months of follow-up. For the mean concentrations in resource-poor settings than in
standard infant schedule, iVE was 95% (89–98) after high-income settings.52 Hypotheses for lower immuno-​
2 weeks, 60% (55–64) after 6 months, and 31% (12–48) after genicity include interference by maternal antibodies,
12 months of follow-up (figure 2). We found no significant interference by oral polio vaccines, neutralising factors
difference between the two schedules after 2 weeks of present in breastmilk, malnutrition, other enteric
follow-up, but strong evidence that the neonatal schedule coinfections, rotavirus strain diversity, and HIV infection.
had higher iVE after 6 months and 12 months of follow-up. Competition in the gut has also been proposed as a reason
The median difference in iVE was 3% (–1 to 10, p=0·088) for the lower performance of oral polio vaccine in
after 2 weeks of follow-up, 17% (13 to 22, p=0·00049) after resource-poor settings.53–55 Research is underway to assess
6 months, and 26% (13 to 48, p=0·017) after 12 months. the role of maternal antibodies and gut microbiota in the
We used a simple power function for the head-to-head immune response to rotavirus vaccines in British,
analyses because it required the minimum number of Malawian, and Indian infants.56 Two pivotal cohort studies
assumptions and parameters and had favourable DIC from Mexico57 and India58 have reported contrasting
scores (appendix p 8). Results for alternative functions estimates of the protection conferred by natural infections
are also shown in the appendix (p 19). against subsequent disease. In Mexico (a medium-
The only other trial with head-to-head comparison of mortality setting), two previous infections (asymptomatic
schedules was a multicountry trial comparing infant or symptomatic) conferred 100% protection against

www.thelancet.com/infection Vol 19 July 2019 723

 Articles
subsequent moderate or severe rotavirus gastroenteritis.
In India (a high-mortality setting), the equivalent pro-​
tection was 57% after two previous infections (and 79%
after three previous infections). If natural infections are
less likely to protect against moderate and severe rotavirus
gastroenteritis in higher-mortality settings than in lower-
mortality settings, then a live oral vaccine mimicking
natural infection might also have lower estimated efficacy
in children in these settings.
The reported declines in instantaneous efficacy might
not be entirely caused by declining vaccine-induced
antibodies. Some of the decrease could be explained by a
higher incidence of natural asymptomatic and mild
infections (and thus preferential immune boosting)
among unvaccinated controls compared with vaccine
recipients. In these circumstances the risk of severe
rotavirus gastroenteritis in vaccine recipients would
gradually converge with, and might exceed, the risk in
unvaccinated controls over time. This phenomenon has
been described previously in the context of so-called
leaky vaccines.59 Our analysis of the infant and neonatal
schedules for RV3-BB in Indonesia suggested a positive
protective effect of the vaccine in the first 18 months of
follow-up, but extrapolation of the curves suggested a
negative effect thereafter. This would be consistent
with preferential natural boosting among non-vaccine
recipients but is speculative, because it involves extra-​
polating beyond the observed period of follow-up in the
trial. Reanalysis of data from an RCT in Bangladesh60 has
allowed these effects to be partly disentangled by
excluding any children who had an episode of non-severe
rotavirus gastroenteritis. This finding explained some,
but not all, of the reduction in vaccine efficacy over time.
However, it was not possible to exclude infants who had
previous asymptomatic infections, which might also
have an important role.
Head-to-head comparisons of schedules for the same
vaccine were rare, and more evidence is needed from
more places on the relative benefits of one schedule over
another. In our analysis of RV3-BB in Indonesia, the
neonatal schedule provided more durable protection
than the infant schedule, but this analysis was based on
few case counts in each week of follow-up. A neonatal
schedule is also likely to result in higher and earlier
coverage and fewer vaccine-related intussusception
events than an infant schedule, so warrants serious
consideration. Other strategies that could help to improve
the effect of the vaccines include administering a booster
dose later in infancy17,61 or using injectable non-replicating
vaccines,62 but more evidence is needed on the safety and
clinical efficacy of both of these options.
For the pooled analysis, we combined evidence for
different vaccine products and different infant schedules
to avoid having small numbers of data points in each
stratum. None of the RCTs compared different brands
of rotavirus vaccination head to head in the same
population. There were several observations for RotaTeq
724 www.thelancet.com/infection Vol 19 July 2019
and Rotarix, but the Rotarix sites included data points
from South Africa, which had higher efficacy and lower
child mortality relative to the sites evaluated in the
RotaTeq trials. Thus, in the absence of head-to-head
comparisons from the same trial populations, there is
insufficient evidence to favour one product over another
in terms of vaccine efficacy and duration of protection.
However, the postlicensure experience of countries that
have used both Rotarix and RotaTeq does not suggest any
material difference in vaccine effect.63
Most of the data points were reported against the
Vesikari 11–20 scale, but some were reported against the
Clark 16–24 scale. These two scores correlate poorly with
one another when estimating the proportion of rotavirus
gastroenteritis episodes defined as severe.64,65 However,
this bias is unlikely to change the conclusion that
protection is high and durable in the low-mortality
stratum, in which the Clark scale was more commonly
used.
We stratified our results by mortality and presented
pooled results with and without data points from
potentially influential studies. We restricted the analysis
to RCTs because they represent the gold standard
approach for measuring per-protocol vaccine efficacy and
provide accurate information about the mean duration of
follow-up. Other designs, such as case-control studies, do
not permit precise estimation of the mean duration of
follow-up. Some case-control studies report vaccine
effectiveness by age band, and thus could potentially be
used to derive the duration of follow-up, but this
approach becomes increasingly crude as the width of the
age band increases. Case-control studies are also at risk
of bias because infants who have been vaccinated might
be different from those who are unvaccinated for both
known and unknown reasons. We also restricted the
analysis to per protocol rather than by intention to treat
because this analysis provided a consistent basis for
pooling the different RCTs, ensuring that all infants
received the recommended number of doses and that a
more consistent starting point was used for the
measurement of follow-up. Accurate estimates of iVE
following a single dose of rotavirus vaccination would be
useful for informing the potential effects of different
schedules, but typically there are few infants who receive
only a single dose, and even fewer of those infants are
followed up for the full duration of the trial.
We reported the initial peak efficacy starting at 2 weeks
of follow-up because of uncertainty around the time that
antibodies might take to develop after vaccination. In
addition, we had to extrapolate our fitted estimates of VE
to periods without empirical data (eg, beyond 2 years of
follow-up). The absence of empirical data from RCTs is
represented by larger credible intervals in these periods.
However, this makes comparison of different waning
functions difficult. Evidence from RCTs with a longer
duration of follow-up or high-quality observational
studies is needed to overcome this knowledge gap. A

so-called no-waning model required only one parameter,
and for this reason had favourable DIC scores in each of
the pooled analyses. However, in Indonesia, where all
data points were from the same trial, the DIC score was
unfavourable. We considered no waning (or no change in
RR) to be implausible, given that VE was shown to
decrease in nearly all RCTs with more than one follow-up
point. However, more studies with multiple follow-up
times would be needed to have greater certainty about
the appropriate form of vaccine waning.
We used a novel approach to convert estimates from
cumulative VE to iVE. We show that this method is able
to retrieve iVE, and that standard estimates of
cumulative VE might overestimate iVE in the presence
of waning. However, there are some limitations in
applying this method to the meta-regression used in
this study. First, it would be better to use relative rates
than RR. We had to compute relative risks because most
of the RCTs only reported observed numbers of cases
and individuals at a limited number of follow-up times.
However, because severe rotavirus gastroenteritis is a
relatively rare outcome, risk ratios and rate ratios are
expected to be similar, and we assume that this bias is
negligible in our study. Second, waning of vaccine
efficacy (or conversely, waxing of the relative rate) might
interact with changes in baseline rates. This effect
would be relatively small on the estimated VE, but
might be pronounced when converted to an iVE.
Because we had no information on changes in the
baseline rates in our studies, we assumed that this rate
was constant over time (an assumption that is often
made in survival analyses) and did not correct for it. The
bias is likely to be in the direction of increasing VE
because baseline rates decline with age, particularly in
high-mortality settings. Our method should ideally be
extended to control for different changing baseline rates
in different studies, as would be the case in a pooled
analysis. However, even uncorrected iVE should still be
a better approximation to true iVE than cumulative VE
in the presence of waning.
Because the two Indian studies had larger sample sizes
than other studies in the high-mortality stratum, we
did a sensitivity analysis to see whether these studies
significantly influenced our results. Exclusion of these
studies did not alter our findings significantly. Moreover,
an analysis in which we estimated iVE for India alone did
not provide meaningful results, because there were only
four observations, which is too few to generate a reliable
pooled estimate in our analysis.
Reviews of the efficacy, effectiveness, and effects of
rotavirus vaccines19,66,67 have described variation in rotavirus
vaccine effects according to under-5 mortality and
geographical region. However, to our knowledge, our
study is the first to synthesise all the available RCT evidence
and to obtain robust estimates of iVE by duration of
follow-up. Our study should provide important evidence
for estimating and monitoring the effects of rotavirus
www.thelancet.com/infection Vol 19 July 2019 725
Articles
vaccines in different settings. Our analysis provides the
most comprehensive evidence to date that rotavirus
vaccine efficacy is lower and wanes more rapidly in high-
mortality settings than in low-mortality settings. The
earlier peak age of disease in these settings means that
live oral rotavirus vaccines are still likely to provide
substantial benefit, but strategies with the potential to
further increase the effects of vaccines, such as neonatal
vaccination, warrant serious consideration. Monitoring
the age distribution of rotavirus disease cases in the years
following vaccine introduction will also be important.
Consistent with the basic theory of infectious disease
dynamics, a reduction in the incidence of infection (eg,
from vaccination) should lead to an increase in the mean
age of infection. As more children become infected at
older ages, the need for more durable rotavirus vaccines
might become more pressing.
Contributors
AC devised the idea for the study, extracted the data, ran preliminary
statistical analyses, and wrote the first draft of the paper. KVZ developed
the methods for converting cumulative vaccine efficacy into instantaneous
efficacy, ran the Bayesian meta-regressions, and designed the figures.
SF, CS and MJ ran preliminary statistical analyses and provided
conceptual and methodological guidance. JB, JT and UP contributed to
data interpretation. All authors provided comments on the draft.
Declaration of interests
JB reports project grants from the Bill & Melinda Gates Foundation and
the National Health and Medical Research Council for the conduct of
clinical trials of the RV3-BB rotavirus vaccine at MCRI, and other
support from the Victorian Government Operational Infrastructure
Support Program. All other authors declare no competing interests.
Acknowledgments
This work was supported by the Bill & Melinda Gates Foundation
(grant number OPP1147721) and the Vaccine Impact Modelling
Consortium (grant number OPP1157270). The views expressed are those
of the authors and not necessarily those of the Consortium or its
funders. SF is funded through a Sir Henry Dale Fellowship jointly
funded by the Wellcome Trust and the Royal Society (grant number
208812/Z/17/Z). We would like to acknowledge the WHO Immunization
and Vaccines Related Implementation Research Advisory Committee for
providing useful feedback on the analysis. We also thank Cochrane
Response (Hanna Bergman, Nicholas Henschke, and
Karla Soares-Weiser) for sharing the list of RCTs identified in their
updated systematic review. The findings and conclusions in this report
are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention.
References
1 GBD Diarrhoeal Diseases Collaborators. Estimates of global, regional,
and national morbidity, mortality, and aetiologies of diarrhoeal
diseases: a systematic analysis for the Global Burden of Disease Study
2015. Lancet Infect Dis 2017; 17: 909–48.
2 Lanata CF, Fischer-Walker CL, Olascoaga AC, et al. Global causes of
diarrheal disease mortality in children <5 years of age: a systematic
review. PLoS One 2013; 8: e72788.
3 Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health
Organization-Coordinated Global Rotavirus Surveillance Network.
Global, regional, and national estimates of rotavirus mortality in
children <5 years of age, 2000–2013. Clin Infect Dis 2016;
62 (suppl 2): S96–105.
4 Rheingans RD, Antil L, Dreibelbis R, Podewils LJ, Bresee JS,
Parashar UD. Economic costs of rotavirus gastroenteritis and
cost-effectiveness of vaccination in developing countries. J Infect Dis
2009; 200 (suppl 1): S16–27.
5 Thomas SL, Walker JL, Fenty J, et al. Impact of the national
rotavirus vaccination programme on acute gastroenteritis in
England and associated costs averted. Vaccine 2017; 35: 680–86.
 Articles
6 Rota Council. Country introductions of rotavirus vaccines.
http://rotacouncil.org/vaccine-introduction/global-introduction-
status/ (accessed Aug 31, 2018).
7 Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and
efficacy of an attenuated vaccine against severe rotavirus
gastroenteritis. N Engl J Med 2006; 354: 11–22.
8 Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a
pentavalent human-bovine (WC3) reassortant rotavirus vaccine.
N Engl J Med 2006; 354: 23–33.
9 Colgate ER, Haque R, Dickson DM, et al. Delayed dosing of oral
rotavirus vaccine demonstrates decreased risk of rotavirus
gastroenteritis associated with serum zinc: a randomized controlled
trial. Clin Infect Dis 2016; 63: 634–41.
10 Cunliffe NA, Witte D, Ngwira BM, et al. Efficacy of human rotavirus
vaccine against severe gastroenteritis in Malawian children in the
first two years of life: a randomized, double-blind, placebo
controlled trial. Vaccine 2012; 30 (suppl 1): A36–43.
11 Madhi SA, Kirsten M, Louw C, et al. Efficacy and immunogenicity
of two or three dose rotavirus-vaccine regimen in South African
children over two consecutive rotavirus-seasons: a randomized,
double-blind, placebo-controlled trial. Vaccine 2012;
30 (suppl 1): A44–51.
12 Zaman K, Dang DA, Victor JC, et al. Efficacy of pentavalent
rotavirus vaccine against severe rotavirus gastroenteritis in infants
in developing countries in Asia: a randomised, double-blind,
placebo-controlled trial. Lancet 2010; 376: 615–23.
13 Kulkarni PS, Desai S, Tewari T, et al. A randomized phase III
clinical trial to assess the efficacy of a bovine-human reassortant
pentavalent rotavirus vaccine in Indian infants. Vaccine 2017;
35: 6228–37.
14 Isanaka S, Guindo O, Langendorf C, et al. Efficacy of a low-cost,
heat-stable oral rotavirus vaccine in Niger. N Engl J Med 2017;
376: 1121–30.
15 Bines JE, At Thobari J, Satria CD, et al. Human neonatal rotavirus
vaccine (RV3-BB) to target rotavirus from birth. N Engl J Med 2018;
378: 719–30.
16 Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Efficacy of
a monovalent human-bovine (116E) rotavirus vaccine in Indian
infants: a randomised, double-blind, placebo-controlled trial.
Lancet 2014; 383: 2136–43.
17 Haidara FC, Tapia MD, Sow SO, et al. Evaluation of a booster dose
of pentavalent rotavirus vaccine coadministered with measles,
yellow fever, and meningitis a vaccines in 9-month-old Malian
infants. J Infect Dis 2018; 218: 606–13.
18 Soares-Weiser K, Bergman H, Henschke N, Pitan F, Cunliffe N.
Vaccines for preventing rotavirus diarrhoea: vaccines in use.
Coch Data Syst Rev 2019; published online March 25.
DOI:10.1002/14651858.CD008521.pub4.
19 Lamberti LM, Ashraf S, Walker CL, Black RE. A systematic review
of the effect of rotavirus vaccination on diarrhea outcomes among
children younger than 5 Years. Pediatr Infect Dis J 2016; 35: 992–98.
20 Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of
numerical scores for clinical severity of diarrhoeal episodes.
Scand J Infect Dis 1990; 22: 259–67.
21 Clark HF, Borian FE, Bell LM, Modesto K, Gouvea V, Plotkin SA.
Protective effect of WC3 vaccine against rotavirus diarrhea in
infants during a predominantly serotype 1 rotavirus season.
J Infect Dis 1988; 158: 570–87.
22 UN, Department of Economic and Social Affairs, Population
Division (2017). world population prospects: the 2017 revision,
DVD edition. http://esa.un.org/wpp/ (accessed Oct 1, 2018).
23 Altman DG. Confidence intervals for the number needed to treat.
BMJ 1998; 317: 1309–12.
24 Daly LE. Confidence limits made easy: interval estimation using
a substitution method. Am J Epidemiol 1998; 147: 783–90.
25 Deeks JJ, Higgins JPT. Statistical algorithms in review manager 5.1.
https://training.cochrane.org/handbook/statistical-methods-
revman5 (accessed Sept 1, 2018).
26 R: a language and environment for statistical computing.
R Foundation for Statistical Computing, Vienna, Austria. URL
http://www.R-project.org/.
27 Plummer M. rjags: Bayesian graphical models using MCMC.
R package version 4-6. https://CRAN.R-project.org/package=rjags
(accessed March 1, 2019).
726 www.thelancet.com/infection Vol 19 July 2019
28 GitHub. R code. https://github.com/kevinvzandvoort/rotavirus_
vaccine_efficacy (accessed Jan 15, 2019).
29 Armah GE, Sow SO, Breiman RF, et al. Efficacy of pentavalent
rotavirus vaccine against severe rotavirus gastroenteritis in infants in
developing countries in sub-Saharan Africa: a randomised,
double-blind, placebo-controlled trial. Lancet 2010; 376: 606–14.
30 Li RC, Huang T, Li Y, et al. Human rotavirus vaccine (RIX4414)
efficacy in the first two years of life: a randomized, placebo-controlled
trial in China. Hum Vaccin Immunother 2014; 10: 11–18.
31 Salinas B, Perez Schael I, Linhares AC, et al. Evaluation of safety,
immunogenicity and efficacy of an attenuated rotavirus vaccine,
RIX4414: a randomized, placebo-controlled trial in Latin American
infants. Pediatr Infect Dis J 2005; 24: 807–16.
32 Tregnaghi MW, Abate HJ, Valencia A, et al. Human rotavirus
vaccine is highly efficacious when coadministered with routine
expanded program of immunization vaccines including oral
poliovirus vaccine in Latin America. Pediatr Infect Dis J 2011;
30: e103–08.
33 Linhares AC, Velazquez FR, Perez-Schael I, et al. Efficacy and safety
of an oral live attenuated human rotavirus vaccine against rotavirus
gastroenteritis during the first 2 years of life in Latin American
infants: a randomised, double-blind, placebo-controlled phase III
study. Lancet 2008; 371: 1181–89.
34 Mo Z, Mo Y, Li M, et al. Efficacy and safety of a pentavalent live
human-bovine reassortant rotavirus vaccine (RV5) in healthy
Chinese infants: a randomized, double-blind, placebo-controlled trial.
Vaccine 2017; 35: 5897–04.
35 Vesikari T, Itzler R, Matson DO, et al. Efficacy of a pentavalent
rotavirus vaccine in reducing rotavirus-associated health care
utilization across three regions (11 countries). Int J Infect Dis 2007;
11 (suppl 2): S29–35.
36 Grant LR, Watt JP, Weatherholtz RC, et al. Efficacy of a pentavalent
human-bovine reassortant rotavirus vaccine against rotavirus
gastroenteritis among American Indian children. Pediatr Infect Dis J
2012; 31: 184–88.
37 Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus
vaccine against rotavirus gastroenteritis during the first 2 years of life
in European infants: randomised, double-blind controlled study.
Lancet 2007; 370: 1757–63.
38 Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live
attenuated human rotavirus vaccine in Finnish infants.
Pediatr Infect Dis J 2004; 23: 937–43.
39 Kawamura N, Tokoeda Y, Oshima M, et al. Efficacy, safety and
immunogenicity of RIX4414 in Japanese infants during the first two
years of life. Vaccine 2011; 29: 6335–41.
40 Phua KB, Lim FS, Lau YL, et al. Rotavirus vaccine RIX4414 efficacy
sustained during the third year of life: a randomized clinical trial in
an Asian population. Vaccine 2012; 30: 4552–57.
41 Bernstein DI, Sack DA, Rothstein E, et al. Efficacy of live, attenuated,
human rotavirus vaccine 89–12 in infants: a randomised
placebo-controlled trial. Lancet 1999; 354: 287–90.
42 Vesikari T, Itzler R, Karvonen A, et al. RotaTeq, a pentavalent
rotavirus vaccine: efficacy and safety among infants in Europe.
Vaccine 2010; 28: 345–51.
43 Block SL, Vesikari T, Goveia MG, et al. Efficacy, immunogenicity, and
safety of a pentavalent human-bovine (WC3) reassortant rotavirus
vaccine at the end of shelf life. Pediatrics 2007; 119: 11–18.
44 Iwata S, Nakata S, Ukae S, et al. Efficacy and safety of
pentavalent rotavirus vaccine in Japan: a randomized, double-blind,
placebo-controlled, multicenter trial. Hum Vaccin Immunother 2013;
9: 1626–33.
45 Clark HF, Bernstein DI, Dennehy PH, et al. Safety, efficacy, and
immunogenicity of a live, quadrivalent human-bovine reassortant
rotavirus vaccine in healthy infants. J Pediatr 2004; 144: 184–90.
46 Feikin DR, Laserson KF, Ojwando J, et al. Efficacy of pentavalent
rotavirus vaccine in a high HIV prevalence population in Kenya.
Vaccine 2012; 30 (suppl 1): A52–60.
47 Vesikari T, Prymula R, Schuster V, et al. Efficacy and immunogenicity
of live-attenuated human rotavirus vaccine in breast-fed and
formula-fed European infants. Pediatr Infect Dis J 2012; 31: 509–13.
48 Vesikari T, Karvonen A, Ferrante SA, Ciarlet M. Efficacy of the
pentavalent rotavirus vaccine, RotaTeq(R), in Finnish infants up to
3 years of age: the Finnish Extension Study. Eur J Pediatr 2010;
169: 1379–86.

49 Vesikari T, Karvonen A, Ferrante SA, Kuter BJ, Ciarlet M.
Sustained efficacy of the pentavalent rotavirus vaccine, RV5, up to
3.1 years following the last dose of vaccine. Pediatr Infect Dis J 2010;
29: 957–63.
50 Armah GE, Kapikian AZ, Vesikari T, et al. Efficacy, immunogenicity,
and safety of two doses of a tetravalent rotavirus vaccine RRV-TV in
Ghana with the first dose administered during the neonatal period.
J Infect Dis 2013; 208: 423–31.
51 Hasso-Agopsowicz M, Nanji Ladva C, Lopman B, et al. Global
review of the age distribution of rotavirus disease in children aged
<5 years before the introduction of rotavirus vaccination.
Clin Infect Dis 2019; published Jan 28. DOI:10.1093/cid/ciz060.
52 Patel M, Glass RI, Jiang B, Santosham M, Lopman B, Parashar U.
A systematic review of anti-rotavirus serum IgA antibody titer as
a potential correlate of rotavirus vaccine efficacy. J Infect Dis 2013;
208: 284–94.
53 Chan J, Nirwati H, Triasih R, et al. Maternal antibodies to rotavirus:
could they interfere with live rotavirus vaccines in developing
countries? Vaccine 2011; 29: 1242–47.
54 Lopman BA, Pitzer VE. Waxing understanding of waning
immunity. J Infect Dis 2018; 217: 851–53.
55 Taniuchi M, Platts-Mills JA, Begum S, et al. Impact of enterovirus
and other enteric pathogens on oral polio and rotavirus vaccine
performance in Bangladeshi infants. Vaccine 2016; 34: 3068–75.
56 Sindhu KN, Cunliffe N, Peak M, et al. Impact of maternal
antibodies and infant gut microbiota on the immunogenicity of
rotavirus vaccines in African, Indian and European infants: protocol
for a prospective cohort study. BMJ Open 2017; 7: e016577.
57 Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infection in
infants as protection against subsequent infections. N Engl J Med
1996; 335: 1022–28.
58 Gladstone BP, Ramani S, Mukhopadhya I, et al. Protective effect of
natural rotavirus infection in an Indian birth cohort. N Engl J Med
2011; 365: 337–46.
www.thelancet.com/infection Vol 19 July 2019 727
Articles
59 Smith PG, Rodrigues LC, Fine PE. Assessment of the protective
efficacy of vaccines against common diseases using case-control
and cohort studies. Int J Epidemiol 1984; 13: 87–93.
60 Rogawski ET, Platts-Mills JA, Colgate ER, et al. Quantifying the
impact of natural immunity on rotavirus vaccine efficacy estimates:
a clinical trial in Dhaka, Bangladesh (PROVIDE) and a simulation
study. J Infect Dis 2018; 217: 861–68.
61 Burnett E, Lopman BA, Parashar UD. Potential for a booster dose of
rotavirus vaccine to further reduce diarrhea mortality. Vaccine 2017;
35: 7198–03.
62 Kirkwood CD, Ma LF, Carey ME, Steele AD. The rotavirus vaccine
development pipeline. Vaccine 2017; published online April 7.
DOI:10.1016/j.vaccine.2017.03.076.
63 Immergluck LC, Parker TC, Jain S, et al. Sustained effectiveness of
monovalent and pentavalent rotavirus vaccines in children. J Pediatr
2016; 172: 116–20.
64 Aslan A, Kurugol Z, Cetin H, Karakaslilar S, Koturoglu G.
Comparison of Vesikari and Clark scales regarding the definition of
severe rotavirus gastroenteritis in children. Infect Dis 2015;
47: 332–37.
65 Givon-Lavi N, Greenberg D, Dagan R. Comparison between
two severity scoring scales commonly used in the evaluation of
rotavirus gastroenteritis in children. Vaccine 2008; 26: 5798–801.
66 Jonesteller CL, Burnett E, Yen C, Tate JE, Parashar UD.
Effectiveness of rotavirus vaccination: a systematic review of the
first decade of global post-licensure data, 2006–2016. Clin Infect Dis
2017; 65: 840–50.
67 Patel MM, Clark AD, Sanderson CF, Tate J, Parashar UD.
Removing the age restrictions for rotavirus vaccination:
a benefit-risk modeling analysis. PLoS Med 2012; 9: e1001330.